Reduction of carbonylic radicals in indolyl-3 compounds



United States Patent REDUCTION OF CARBONYLIC RADICALS m INDOLYL-F:COMPOUNDS Merrill E. Specter, Kalamazoo Township, Kalamazoo County,Mich., assignor to The Upjohn Company, mazoo, Mich, a corporation ofMichigan No Drawing. Application Aprii 11, 1955 Serial No. 530,669

The present invention relates to a novel process for the preparation ofl-dehydro-3-(2-amino-l-hydroxyethyl)-indoles and to the novel compoundsproduced therein. More particularly, the invention is concerned with thereduction of 1-dehydro-3-indoleglyoxylamides andl-dehydro-3-indoleglycolamides with lithium aluminum hydride to producethe novel 1-dehydro-3-(Z-amino-l-hydroxyethyD-indoles and to novel1-dehydro-3-indoleglyoxylyl halides, 1-dehydro-3-indoleglyoxylamides,and l-dehydro-3-indoleglycolamides useful therein. The term dehydro isused to denote the absence of hydrogen in the l-position of the indolenucleus in contrast to a 1- hydroindole.

It is known that 1-hydro-3-indoleglyoxylic acid esters can be reducedwith aluminum amalgam (Baker, J. Chem. Soc. 1940, 458-60), but in thedisclosed Baker process the ring-attached carbonyl group is reduced onlyto a carbinol group and the carboxylic carbonyl is not reduced at all.Thus when Baker reduced 1-hydro-3-indoleglyoxylic acid esters (themethyl or ethyl ester) with aluminum amalgam, he obtained thecorresponding 1- hydro-3-indoleglycolate. It is known also that certainglyoxylic acids can be reduced with lithium aluminum hydride. By thisprocess, however, the corresponding ethylene glycol is obtained. Thusphenylglyoxylic acid was reduced by Nystrom et al., I. Am. Chem. Soc.69, 2548-9 (1947) to phenylethylene glycol.

It has now been found that 3-indoleglyoxylamides react with lithiumaluminum hydride in an entirely unexpected manner. Thus when the3-indoleglyoxylamides are unsubstituted in the l-position, i. e., are1-hydro-3- indoleglyoxylamides, the carboxylic carbonyl group and thering-attached carbonyl group are reduced to methylene groups to produce3-(2-aminoethyl)-indoles (tryptamines), but when the3-indoleglyoxylamides are substituted in the 1-position, i. e. arel-dehydro-S-indoleglyoxylamides, the carboxylic carbonyl group iscompletely reduced to a methylene group and the ring attached carbonylgroup is reduced to a carbinol group to produce 1- dehydro-3-(Z-amino-l-hydroxyethyl) -indoles.

it has been further found that 3-indoleglycolamides react with lithiumaluminum hydride in a like anomolous manner. Thus withl-hydro-3-indoleglycolamide, the carboXylic carbonyl group as well asthe carbinol group is reduced to methylene groups, but with 1-dehydro-3-indoleglycolamides, the carboxylic carbonyl group is reduced to amethylene group and the carbinol group remains intact.

The process to which the present invention is directed, namely, thepreparation of l-dehydro-3-(2-amino-l-hydroxyethyD-indoles, isapplicable to any l-dehydro-S-indoleglyoxylamide and1-dehydro-3-indoleglycolamide. The indole nucleus, other than the 1 and3 position, can be substituted or unsubstituted. Substituents reduciblewith lithium aluminum hydride under the conditions of the presentinvention are usually undesirable unless the reduced form of thesubstituent is desired in the final product.

ice

It has been further found in accordance with the present invention thatthe desired 1-dehydro-3-(2-amino-1- hydroxyethyl)-indoles, wherein thel-substituent is alkyl or aralkyl, can be obtained in high yield byconverting a 1,3-dihydroindole to a l-alkyl or 1-aralkyl-3-hydroindole(the 3-position has to be unsubstituted), subjecting the later toglyoxylation with an oxalyl halide to produce a l-alkyl orl-aralkyl-3-indoleglyoxylyl halide, converting the latter to an amide byreacting with ammonia or a primary or secondary amine, and reducing theresulting l-alkyl or l-aralkyl-3-indoleglyoxylamide with lithiumaluminum hydride. By this process a 1,3-dihydroindole can be convertedto the desired l-alkyl or l-aralkyl-3-(2- amino-l-hydroxyethyl)-indolein four smiple steps, each of which gives a high yield.1-aryl-3-(2-amino-1-hydroXyethyD-indoles can also be prepared bysubjecting a l-aryl-3-hydroindole to glyoxylation with an oxalyl halide,amidating the resulting 1-aryl-3-indoleglyoxylyl halide with ammonia ora primary or secondary amine, and reducing the resulting amide withlithium aluminum hydride. l-aryl-S-hydroindoles, e. g., l-phenylindole,can be prepared by the Fischer synthesis. For example, Shirley et al.,I. Am. Chem. Soc. 75, 375 (1953), describe the preparation ofl-phenylindole by the ring closure of the diphenylhydrazone of pyruvicacid followed by decarboxylation of the resulting1-phenyl-2-indolecarboxylic acid.

An alternative process for the preparation of a l-alkyl orl-aralkyl-3-indoleglyoxylamide involves subjecting a 1,3-dihydroindoleto glyoxylation with an oxalyl halide, converting the resulting1-hydro-3-indoleglyoxylyl halide by amidation to a1-hydro-3-indoleglyoxylamide, and thereupon converting the1-hydro-3-indoleglyoxylamide to a l-alkyl or al-aralkyl-3-indoleglyoxylamide.

Introduction of alkyl or aralkyl substituents at position 1 can beaccomplished by the process described by Baker (100. cit.), i. e., thedesired l-substituent can be introduced into a 1,3-dihydroindole beforeglyoxylation or into a 1-hydro-3-indoleglyoxylamide, as noted above. TheBaker process involves reacting a l-hydroindole with an alkyl halide inthe presence of an alkali-metal alkoxide for the preparation of al-alkylindole. An aralkyl halide, e. g., benzyl chloride, can also beemployed in the Baker process for the preparation of a l-aralkylindole.Moreover, l-alkyl or l-aralkylindoles can also be prepared by the wellknown Fischer synthesis. Potts et al., J. Chem. Soc. 1954, 2641, andPlieninger, Ber. 87, 127 (1954) also describe the preparation ofl-substituted indoles.

A further modification of the process of the present invention involvesthe partial reduction of a l-dehydro-3- indoleglyoxylamide to a1-dehydro-3-indoleglycolamide by employing a reducing agent other thanlithium aluminum hydride, e. g., sodium borohydride, and thereuponcompleting the reduction with lithium aluminum hydride to the desiredl-dehydro-3-(2-amino-1-hydroxyethyl)-indole.

For the purpose of more fully illustrating the present invention, thestarting 3-hydroindoles, for the most part, can be represented by thefollowing formula:

r 73 substituted phenyl and naphthyl such as chlorophenyl, 2-chloronaphthyl, and the like; an aralkyl radical, e. g., benzyl,phenethyl, haloaralkyl such as para-chlorobenzyl, alkylaralkyl such aspara-ethylbenzyl, alkoxyaralkyl -such as para-methoxybenzyl, and thelike; or a lower-alkyl radical containing up to and including eightcarbon atoms, e. g., methyl, propyl, octyl, and the like. R 'representshydrogen; an alkyl radical containing up to twenty carbon atoms such as-rnethyl, ethyl, propyl, hexyl, decyl, hexadecyl, and the like; an arylradical containing up to fifteen carbon atoms such as phenyl, naphthyl,biphenylyl, para-chlorophenyl, Z-ethoxynaphthyl, and the like; oranjaralkyl radical containing up to fifteen carbon atoms such as benzyl,phenethyl, phenylbutyl, halobenzyl, such as para-chlorobenzyl,alkylbenzyl, such as para-methylbenzyl,'alkoxybenzyl, such aspara-methoxybenzyl, and .the like. R advantageously contains not morethan fif- -teen carbon atoms and represents halogen, e. g., fluorine,.chlorine, bromine, and iodine; a cyano radical; a carboxy radical; alower-carbalkoXy radical, e. g., ..carbethoxy, 'carbobutoxy, and thelike; a dialkylarnino gradical, e. g, dimethylamirio, diethylamino,methylbutyljamino, and the like; a lower-alkyl radical; an 'arylradical; an aralkyl radical; an aiyloxy radical, e. g., phenoxy, and thelike; a jlower-alkoxy radical, e. g, methoxy, isopropoxy, butoxy, anddislike; a benzyloxy radical, e. g., benzyloiry, benzhydryloity,alkylbenzyloxy, such as paramethylbenzyloxy andpara,para-dimethylbenzhydryloXy,

halobenzyloxy, such as para-chlorobenzyloxy. and para,

'para'-dichlorobenzhydryloXy, 'alkoxybenzyloxy, such aspara-methoxybenzyloxy and para,para-dimethoxybenzhydryloxy, and thelike; an acyloxy radical wherein the acyl substituent is from an organiccarboxylic acid containing .from'one'to eight carbon atoms, e. g.,formyloxy, acetoxy, propionoi y, benzoxy, andthe like; and a fusedarylene radical, e. g., phenylene, naphthylene, and the like. It is .aninteger from zero to four, and when n isgreater than one the R s can'bealike or different. When n is less than four, ofcourse, it is understoodthat the remaining benzene-ring positions are not substituted. A fusedarylene radical, as used herein, encompasses a divalent ,aryle'neradical which is fused at positions e, f, or g of the benzene ring ofthe indole nucleus.

It is to be understood, however, that the invention in itsbroadestaspects, is independent of the presence or vabsence ofsubstituents on the benzene or pyrrole ring :except, of course, that thel-hydrogen must be replaced;

also that the invention is independent of the'particular group used toreplace the l-hydrogen as long as the 1- hydrogen is not regenerated byhydrogenolysis during the reduction;

In all other respects the indole nucleus can be unsubstituted'orsubstituted as desired by indifferent substituents, that is,substituents which are not afiected by 'the reagents used in theprocess, or by reactive substituents, that is, substituents which areafiected by the reagents used in the process. If a substituent isaffected by a reagent used, it means only that the substituenton the ,7product willbe different from that on the starting compound and theonlyadverse effect is that more of the re- ;agent will be required to effectthe desired reduction in the 3-substituentgroup. Thus the indole nucleuscan be substituted as desired without afiecting'the characteristic anddesired reduction of the S-substituent'gmup in accordance withtheinvention.

e The various substituted indcles, employed in the preparation of theessential 3-ind'oleglyoxylyl halides can be prepared byone of thefollowing procedures: V 1) The 4- and S-aCyloxyindoles are prepared inthe I mannerdisclosedby Beer et at. (l. ChemfiSocf 1948, ,I605,+9),inithei'preparation of 4-and 5.-'acetoxyindoles by utilization of thecorresponding acylating agent. The fi-ta'nd 7-acyloxyindoles areprepared in the same manner- 'utilizing t-hydroxy-Znitrobenzaldehyde(Sachi'Ber, 39,, 2 758), and 3-hydroXy-2-nitrobenaaldehyde (Hodgson letcarbomethoxy,

73 3 al., J. Chem. Soc. 1925, 877), respectively, as the startingcompounds.

(2) The starting 4-, 5-, 6- and 7-benzyloxyindoles can cohol; and (c)Dehydrating the benzyloxy-2-nitro-tt-il-(l-nitroaIkyDJ-benzyl alcohol byreacting the alcohol with an aliphatic acid anhydride, e. g., aceticanhydride, at a temperature between about fifty and about 150 degreescentigrade, preferably about eighty degrees centigrade, to produce abHZYl0Xy-fi,Z-dillltIOSif/X'finfl; and

(d) subjecting the benzyloxy-fl,Z-dinitrostyrene to reductivecycliz'ation by reacting the styrene with powdered iron in an organicacid medium, such as acetic, propionic, butyric, or the like, at atemperature between about and about 120 degrees centrigrade toproduce'the -7- benzyloxyindole, 6-benzyloxyindole, S-benzyloxyindole,and 4-benzyloxyndole, respectively. f

The starting 4-, 5-, 6-, and 7-h alo, cyano, carboxy, carbalkoxy,dialkylamino; aryl, aralkyl, alkyl, and aryloxy substituted indoles canbe prepared by reacting the corresponding '2-nitrobenzaldehyde with al-nitro- .alkane to prepare the benzyl alcohol, dehydrating, andreductively cyclizing as described above; l (3) The startingalkoxyindoles employed in the process of the present invention areprepared by the procedure outlined by Blaikie et al. (J. Chem. Soc.1924, 296) in the preparation of 4-, 5-, and 7-methoxyindoles ,byutilizing the requisite alkoxy-Z-nitrotoluene. The 6-alkoxyindoles areprepared'bythe procedure employed by Kermack et al. (J. Chem; Soc. 1921,1602);

(4) The preparation of 2-substituted indoles is advan- -hydrazones ofmethyl ketones, is readily applicable to the preparation of2-substituted indoles. Thus, for example,

' Elderfield, Heterocyclic Compounds, vol. '3, page 14,

1952, John Wiley and Sons, shows the cyclization of the phenylhydrazoneof acetophenone to prepare 2-phenylindole. In a similar manner theZ-benzyland 2-naphthylindoles are prepared by utilizing thecorrespondingphenylhydrazine and the corresponding methyl aralkyl (or aryl) ketone.The Fischer synthesis can also be employed to prepare Z-methylindoles byreacting acetone and the corresponding arylhydrazine. The preparation ofother 2 -lower-alkylindoles, is advantageously carried outlby thecondensation of the corresponding benzaldehyde and l-nitroalkane as morefully disclosed above. 7 The starting fused arylene indoles, e; g.',benzindoles, are

prepared 'by the process described by Rydon et al., J.

Chem. Soc. 1951, 2462. j

' On' glyoxylation; the starting 1,3-dihydroindoles are converted tol-hydro-B-indoleglyoxylyl halides having the formula:

TE 0-C-halogen 7 R i i V N i n a -0-2 wherein R R and n have the valuesgiven above, and Z represents a primary, secondary, or tertiary amidoradical. Thus Z can be the amido radical corresponding to ammonia andprimary and secondary amines. The secondary and tertiary amido radicalsthus represented by Z include such radicals as alkylamido, aralkylamido,cycloalkylamido, arylamido, dicycloalkylamido, diaralkylamido,dialkylamido, alkyl aralkylamido, alkyl cycloalkylamido, alkylarylamido, aralkyl cycloalkylarnido, aralkyl arylamido, and cycloalkylarylamido, and Z can also represent a monoheterocyclic amido radical,including amido radicals such as piperidyl, morpholinyl, pyrrolidyl,thiamorpholinyl, hexamethyleneimino, tetrahydroisoquinolyl,hexahydroisoquinolyl, and the like.

In carrying out the process of the present invention thel-hydro-3-indoleglyoxylyl halides are prepared by reacting a1,3-dihydroindole with an oXalyl halide in the presence of an inertorganic solvent, such as ether, petroleum ether, methylcyclohexane,dioxan, and the like. Aromatic hydrocarbons, such as benzene and thelike can also be employed when the acid halide is not to be isolated.Stoichiometric quantities (i. e., equimolar) are advantageouslyemployed. The reaction is advantageously conducted at about degreescentigrade although other temperatures between about ten degreescentigrade and about the boiling point of the solvent employed can alsobe utilized. The reaction is generally completed between about fifteenminutes and about eight hours, longer periods being required for lowerreaction temperatures 7 and/or less reactive indoles. The reactionmixture generally reddens, but soon decolorizes, whereupon a precipitate generally begins to form. After standing be tween about one andabout eight hours, the reaction mixture is cooled to about zero degreescentrigrade whereupon the 1-hydro-3-indoleglyoxylyl halide precipitatecan be recovered by filtration.

In the preparation of l-hydro-3indoleglyoxylarnides, the starting1,3-dihydroindole is first glyoxylated and then subjected to amidationadvantageously by the process of this invention, wherein the1,3-dihydroindole is reacted with an oxalyl halide to form al-hydro-3indoleglyoxylyl halide which is reacted with ammonia or aprimary or secondary amine to form the desired amide. Ammonia isemployed to produce a primary amide, and primary and secondary amines toproduce secondary and tertiary amides, respectively. The amidationreaction is advantangeously conducted at a temperature about zerodegrees and about 100 degrees centrigrade, preferably at about 25degrees centrigrade and is usually completed between about thirtyminutesand about five hours, the longer reaction period being required at thelower temperatures. The reaction is advantageously carried out in thepresence of inert solvents such as aliphatic hydrocarbons, aromatichydrocarbons, ketones, and ethers, with benzene being preferred, but thereaction can also be completed without a solvent.

The lhydro-3indoleglyoxylamides are thereupon converted, e. g., by theBaker process discussed earlier, to 1- alkyl or1aralkyl-B-indoleglyoxylamides having the wherein R R Z and n have thevalues given above and R represents an alkyl radical containing up totwenty carbon atoms such as methyl, ethyl, propyl, hexyl, decyl,hexadecyl, and the like; or an aralkyl radical containing up to fifteencarbon atoms, e. g., benzyl, phenethyLphenylbutyl, halobenzyl, such aspara-chlorobenzyl, alkylbenzyl, such as para-methylbenzyl, alkoxybenzyl,such as paramethoxybenzyl, and the like.

Alternatively, l-dehydro 3 indoleglyoxylamides, wherein thel-substituent is alkyl, aralkyl, or aryl, can be prepared, as discussedearlier, by glyoxylation of the corresponding 1-dehdyro-3-hydroindolesto prepare 1- dehydro-3indoleglyoxylyl halides and subjecting the latterto amidation to produce the l-deyhdro-3-indoleglyoxylamides.

The thus-produced 1-dehydro-3indoleglyoxylamides are reduced withlithium aluminum hydride to produce the corresponding 1 dehydro3-(2-arnino-1-hydroxyethyl)- indoles which, for the most part, can berepresented as having the formula:

wherein R 11 and Z have the values given above. More specifically 2represents wherein R and R represent hydrogen, aryl, aralkyl, and alkyland when taken together with N also represent a. heterocyclic aminoradical. R represents an alkyl radical containing up to twenty carbonatoms, an aryl radical containing up to fifteen carbon atoms, or anaralkyl radical containing up to fifteen carbon atoms; and R representshydroxy, dialkylamino, methylol (Ci-1 0E), aminoniethyl (CH NH halogen,alkyl, aryl, aralkyl, aryloxy, a fused arylene radical, a benzyloxyradical, and a loweralkoxy radical. Reduction of1-dehydro-3-indoleglyoxylamides wherein R as previously identified, isan acyloxy, cyano, carboXy, or a lower-carbalkoxy radical results in theconversion of these substituents to a hydroxy, aminornethyl (CHZNHZ),methylol (CH OH), and methylol radical respectively. The reduction ofthe 1- dehydro-3-indoleglyoxylamides is advantageously carried out inthe presence of an inert solvent such as ether, tetrahydroturan,N-ethylmorpholine, dibutyl ether, and the like, with tetrahydrofuranbeing preferred. The reduction is advantageously accomplished at theboiling point of the solvent used, although other temperatures betweenabout zero and about degrees centigrade can be employed, and preferablyzero to 65 degrees centigrade. After a suitable reaction period, usuallyfrom thirty minutes to five hours, the free bases are readily obtainedas viscous oils, or in some instances in crytalline condition, byhydrolyzing the reaction mixture with aqueous ether fol lowed by dilutealkali, decanting the solvent layer, extracting the alkaline residuewith several portions of ether;

combining the ether extracts and decanted solvent layer, and evaporatingthe solvent. Other conventional procedures for the hydrolysis can beused if desired, and other organic extractants can be used in place ofether.

V r Z-benzylindole,

' fihYPZEPh iil-tc wi e l indo'le, 1 (para-methylbenzyl):2-propyl-6-cyanoindele, 1-

mata or The*1 dehydro 3' (2 1 amino: ,1 hydroxyethyl), iniloles'thus'obtaine'd can beconverted to acid addition salts, if so desired.For example, a solution of the desired acid addition salt can beprepared .by mixing stoichiometric amounts of a free base of theinvention and an inorganic or organic acid in the presence of water.Examples of acids are hydrochloric, hydrobromic, sulfuric, phosphoric,pyruvic, acetic, tartaric, citric, benzoic, trichloroacetic, and thelike. A quaternary ammonium salt such as the methoiodide, ethoiodide,benz yl chloride, and the like may also be prepared by reacting thetertiary amine free base in a. suitable inert solvent with an alkyloraralkyl halide, 1r withidimethyllsulfate, methyl para-toluenesulfonate,andthelike. M

'Ihe; reduction of the' starting l-dehydro 3-indole glyoxylamides'canalso be accomplished in .a stepwise manner, if so desired: For example,the ring-attached carbonyl groupof. thestarting 1-dehydro-3-indoleglyoxylamide canbejzparltially reduced to a carbinol group by utilizingreducing agents other than lithium aluminum hydride, 'e. g., sodiumborohydride, lithium borohydride,

. aluminum amalgam, andcatalytic hydrogenation using platinum oxidecatalyst. Further reduction of theinterrnediate1-dehydro-3-indoleglycolamide With lithium aluminum hydride according tothe process of thepresent in: v'ention will produce the desiredl-dehydro-3-(2-amino-1- hydroxyethyD-indole.

c l The 1-dehydro-3:(2-amino-l-hydroxyethyl)-indo1es and salts producedby the process of the present invention have physiological activity, andmore particularly hypotensive activity'and diuretic activity. Moreover,the present compounds can be reacted .With fluosilicic acid to formfluosilicate salts which in dilute aqueous solution are eflfec- 'tivemothproofing agents, as more fully disclosed'in U. S.

Patents 2,075,359 and 1,915,334. 7 e

The 4-, 5-, 6-, or 7-aralkoxy or alkoxy-l-dehydro-3-(2- amino-l-hydroxyethyl) indoles can be further converted,

' if so desired,-t0 the correspqnding 4-, 5.-, :6-, dr 7 hydroxycompounds by dearalkylation or dealkylation, respectively. Thedearalkylation can be carried out by hydrogenolysis in the presence of acatalyst, advantageously palladium on charcoal. The dealkylation can beaccomplished by treatmentwith aluminum chloride according to theprocedure outlined by Asero et al. [Ann 576, 69-74 (1952)].

Representative S-hydroindoles which can be' employed herein include thefollowing: l-methylindole, l-methyl V 71,2-diethylindole,l-bcnzylindole, lphenethyl 2 'phenylindole, 1 methyl-Zphenylindole, l-

VethyhZ-(para-chlorophenyl)-indo1e, Lethyl 2-"(paraehlorophenyl)-5rmethyl-indole, 1 ethyl 2 L phenyl-S-benzyloxyindole, 1phen ethyl-2-propyl-6-benzyloxyindole, 1 -;hexyl 6benzyloxyindole, l-(para-chlorobenzyl)-5-. (pa ra,para.'dichlorobenzhydryloxy) indole, 1,2 dipropyl '6 ,(para,paradimethylbenzhydryl lyl-indole 1 (para ethoxybenzyl) 2 methyl 5(para,paradiethoxybenzhydryloxyl) -indole, 1- (p ara-methoxybenzyl}5.-(para-methoxyberizyloxy.)-ind0le, lhexyl 4(paramethoxybenzyloxy)-indole, 1 phenethyl 2 phenyl-d(para-propoxybe'nzyloxy indole, 1,2 dioctyl 6'-(paramethylbenzyloxy)rindole, l-(para-ethylbenzyl) 2 ethyl-5-(para-butylbenzyloxy) indole, .71-decyl-6-(paraethylbenzyloxyl)-irldole, 1 (para-c hlorobenzy1) -6-para-chlorobenzyl'oxyHndo-le, 1benzyl-5-(para-bromobenzyloxy)- indole, lpropyl-2-naphthyl-5-methoxyindole, l-methyl- S-methoxyindole,i-ethyl-2-phenyl 5-ethoxyindole,

.2 phenyl-S,7-dichloroindole,

in 200 milliliters of dry benzene;

solid precipitate was filtered, and washed rwit h waters, The

' propyl-4-naphthoxyindole, l ethyl-2-(para-biphenylyl)- indole,1-methyl-Z-(para-biphenylyl)-indole, l-benzyll-phenyl-7-metho xyindole,EZ-diphenylindole, 1-phenyl-2-methylindo1e,' i1? ole, 2 parabiphenylylindole, 2-phenyl-5-methoxy indole, 2.phenyl-6-methylindole, 72fphenylindole, 4- chloroindole, 2 para-biphenylyl-S,7-diehloroindole,2'.

methyl 5,7 dichl-oroindole, 2 -ph enyl 4,7-dichloroindole,

5,6 dimethoxyindole, Z-(para-met-hylphenyl)-5-methylindole, 4-cyanoindole, 4-carb'oxyindole, {Lcarbomethoxyindole, S-bromoindole,Z-methylindole, 5ethylindole, 7-v

r'nethylindole, 2,4 dimethylindole, Z-(para-methoxyphcnyl)5-methoxyindole, 5 benzyloxyindo'le, 6-benzyloxyindole,2-phenyl-5,7-dimethylindole, 2,5-diphenylindole, S-ethoxyindole,2,4,7.-trimethylindole, 2-benzylindole, 5,6-dibromoindole,2-methyl-5,6-dimethoxyindole,

2-methyl-5-fluoroindole, Z-hexylindole, 4-acetoxyindole,

Z-rnethyl-S,-diacetoxyindole, S-methoxy-fi-acetoxyindole, Z-(Z-naphthyl)7 chl'oroindole, 1'-benz-(g)-indole, 5- phenoxyindole,6-dimethylam-inoindole, 2t-butylindole, 7- henzhydr yloxyindole," 4(para-methoxybenzyloxy)- ind-ole, 7-benzylindole,6-(para-chlorobenzyloiry)-indolc,

6 (para,para dimethylbenzhydryloxy)-indole, and the like a T hefollowing examples are illustrative of the process and products of thepresent invention, butare not tobe construed as limiting. EXAMPLEAMINO-l-HYDROXYETHYL)-INDOLE* A: s-inaole l 'ox lyl chloride a w it s f,5 ams. -2 hid o lld lld,

500 milliliters of anhydrous ether was added 25 milli liters (0.29 mole)of oxalyl chloride. The solution 7' turned red and immediately decolorized, followed by the precipitation of a yellow solid. After standingovernight the. solid was collected, washed with dry ether, and dried]under reduced pressure; The compound, 3-indole'gly oxylyl" chloride,weighed degreescentigrade. H V

B. N-ntethyl-3-indoleglyoxylamide V Gaseous methylamine was passed.into; a suspension, of

twenty grams (0.l mole) of 3-indoleglyoxylyl chloride product,N-methyl-3-indoleglyoxylamide, was recrystallized from isopropanol andmelted at 213-219, degrees c'entigradei The yield was 19.6 grams 97percent).

Analysis.Calcd. for CnHmNgOzi C, H,

' N, 13.86. .Foundi c, 65.72 113.52; N,'13;9o.

dibe n zyl 5,6 diethoiryindole, 1 methyl-5,6-diacetoxyclilorobenzyl) :2benz yl; 6 Jou'tyroxyindoie, ,l-pheuh xa y r svmindq l-tpmaor v ll-r abethoxy le, 1 1 cy 'e 4 c ree i are,

C: 1,N-dimethylfirindoleglyoxylarnide 1'- A solution; of sodium ethoxidewas prepared from 400' milliliters of absolute ethanol and'2.76 molesofiso dium- To this solution, was added 20.2 grams: (0.1 mole} of Nmethyl-34ndoleglyorrylamide and the mixture was: placed in a pressurefiask. Afiter the addition of. 1 4.2 grams (0.1 mole) of methyl iodidethe flaskwas'sealed and the mixtureheated'at ,75 degrees eentigra'degforDuring, his P r l matie eighteen hours. crystals, separated. These werefiltered and the filtrate.

concentrated. iThe recrystallized product, l,N -dimeth yl-QS-indoleglyoxylamide, melted at 20620 7 d egrees ce ritif' ihe e d s i he r ms .(83.-51 r t),- V

l-phenyl- 42 grams andmelted at 129;

After two hours the.

s s-amt A. D. 1-methyl-3-(2-methylamin0-1 -hydroxyethyl) -indle Fivegrams (0.023 mole) of 1,N-dimethyl-3-indoleglyoxylamide was dissolved in400 milliliters of tetrahydrofuran. This solution was added to fivegrams (0.13 mole) of lithium aluminum hydride dissolved in 100milliliters of tetrahydrofuran. After refluxing the mixture for threehours the source of heat was removed and the flask cooled in anice-bath. The excess reducing agent was destroyed through addition of500 milliliters of USP ether followed by fifty milliliters of tenpercent sodium hydroxide solution. The clear solvent layer was decantedand concentrated at low temperature under reduced pressure. Theremaining oil crystallized; upon recrystallization from ethyl acetatethe product melted at 137-139 degrees centigrade. A secondrecrystallization gave 3.5 grams (74.7 percent) of 1-methyl-3-(2-methylamino-l-hydroxyethyl)-indole which melted at 138-140 degreescentigrade.

, Analysis.-Calcd. for C H N O: C, 70.56; H, 7.90; N, 13.72. Found: C,70.81; H, 7.90; N, 13.42.

EXAMPLE 2.--PREPARATION OF l-METHYL-B-(Z-BENZYL- METHYLAMINO-l-Hvonoxvnrnvr.) -INDOLB A. N -benzyl-N methyl-3-indolegly0xylamide To asuspension of 31 grams (0.15 mole) of 3-indoleglyoxylyl chloride,prepared as disclosed in Example 1, part A, in 500 milliliters ofbenzene was added 38.72 grams (0.32 mole) of benzylmethylamine. Themixture became hot and a heavy precipitate formed. After three hours thesolid was filtered and washed with water. A small amount of additionalsolid was isolated from the benzene filtrate by concentration. Thecombined solids were recrystallized from isopropanol and 42 grams (87percent yield) of N-benzyl-N-methyl-3-indoleglyoxy1- amide, melting at172.5-173.5 degrees centigrade, was isolated.

Analysis.Calcd. for C H N O C, 73.95; H, 5.52; N, 9.58. Found: C, 74.22;H, 5.29; N, 9.86.

B. L N-dimethyl-N-benzyl-3-ind0legly0xylamide C.1-methyl-3-(Z-benzylmethylamino-l -hydr0xyethyl) indole Ten grams (0.03mole) of 1,N-dimethyl-N-benzy1-3- indoleglyoxylamide was reduced intetrahydrofuran solution with 7.4 grams (0.2 mole) of lithium aluminumhydride in the same manner as in Example 1, to produce1-methyl-3-(2-benzylmethylamino 1 hydroxyethyl) -indole.

EXAMPLE 3.-PREPARATION or 1-METHYL-3-(2-MORPHO- LINO-l-HYDROXYETHYL)-INDOLE A. 3-ind0leglyoxylic acid morpholide A solution of fifty gramsof indole and 1250 milliliters of anhydrous ether was mixed with 45milliliters of oxalyl chloride. After about thirty minutes theprecipitate was collected and added to one thousand milliliters ofanhydrous benzene containing 135.5 grams of morpholine. :.The resultingpaste was vigorously stirred for one hour, and 75 milliliters of. waterwas added thereto The resulting precipitate was collected after stirringfor about thirty minutes, washed thoroughly with benzene, slurried inwater, filtered, and dried. The yield of 3-indoleglyoxylic acidmorpholide was 101.3 grams; the melting point, after recrystallizationfrom alcohol, was 182-184 degrees centigrade.

Analysis.-Calcd. for C I-1 N 0 C, 65.09; H, 5.46; N, 10.84. Found: C,65.25; H, 5.15; N, 10.85.

B. 1-methyl-3-indoleglyoagylic acid morpholide A solution of 1.6 grams(0.07 mole) of sodium was prepared in 200 milliliters of absoluteethanol. To the solution was added 12.9 grams (0.05 mole) of3-indoleglyoxylic acid morpholide and 14.9 grams (0.1 mole) of methyliodide. The mixture was placed in a pressure flask and heated at seventydegrees for sixty hours. The mixture crystallized on cooling andthesolid was filtered and recrystallized from isopropanol. The product, 1-methyl-3-indoleglyoxylic acid morpholide, melted at 177- 178.5 degreescentigrade.

Analysis.Calcd. for C H N O C, 66.15; H, 5.92; N, 10.84. Found: C,66.49; H, 5.80; N, 10.20.

C. 1-methyl-3-(Z-morpholino-l-hya'roxyethyl) indole Seven grams (0.03mole) of 1-methyl-3-indoleglyoxylic acid morpholide was dissolved in 75milliliters of tetrahydrofuran. This solution was added to 3.7 grams(0.1- mole) of lithium aluminum hydride dissolved in 200 milliliters oftetrahydrofuran. The mixture was refluxed for two hours and cooled in anice-bath.- The mixture was treated with 500 milliliters of U. S. P.ether fol lowed by 25 milliliters of ten percent sodium hydroxidesolution. The solvent layer was decanted and the alkali layer Washedwith several 100-milliliter portions of ether. The combined solventswere concentrated under reduced pressure and the remaining oil sooncrystallized. The solid gave a brilliant red color with strong acid. Aninfrared spectrum of the material indicated the presence of a hydroxylgroup. Analytical data was in agreement with this indication. Theproduct, l-methyl -3 (2- morpholino-l-hydroxyethyl)-indole, melted at99-100 degrees centigrade after two recrystallizations from ethylacetate.

Analysis.-Calcd. for C I-1 N 0 C, 69.20; N, 10.76. Found: C, 69.37; H,7.85; N, 10.88.

EXAMPLE 4.PREPARATION OF l-METHYL-3-(2-BENZYL-AMINO-l-HYDROXYE'IHYL)-INDOLE A. N-benzyl-3-ind0leglyoxylaiitia'ehundred milliliters of Skellysolve B. The product, N-

benzyl-3indoleglyoxylamide, was collected, washed with water, and dried.A yield of 21.1 grams was obtained and the product melted at 172-1735degrees centigrade.

Analysis.Calcd. for C I-1 N 0 C, 73.36; H, 5.07; N, 10.07. Found: C,73.66; H, 5.11; N, 10.33.

B. 1-methyl-N-benzyl-3-ind0legly0xylamide A solution of sodium ethoxidein absolute ethanol was prepared from 4.6 grams (0.2 mole) of sodium and800 milliliters of absolute ethanol. To this was added 27.8 grams (0.1mole) of N-benzyl-3-indoleglyoxylamide. The mixture was placed in apressure flask with 21.6 grams (0.15 mole) of methyl iodide and warmedto eighty degrees centigrade for 72 hours. The cooled mixture wasconcentrated'under reduced pressure and the residue washedwithwater.to-remove sodium iodide.

1;). 1 ez'hyl 3 2 uct, 1-methyl-N benzyl-3-indoleglyoxylamide, melted at141.5-143 degrees centigrade. 1 V Anqlysis.+calcd. .fr C 1 H16 N202: C,H, N, 9.58. Found: C, 74,07;jI-I, 5.01; N, 9.79. r

C. 1-methyl-3- (Z-benzylamino-I-hydmxyefhyl) -ind0le Ten grams (0.03mole) of,.l-methyhNzbenzylfi-inr doleglyoxylamide was dissolved in 100milliliters of tetrahydrofuran andadded to a solution of five grams(0.135 mole) of lithium aluminum hydride in 200 milliliters oftetrahydrofuran. The mixture was refluxed for threehours and the crudeproduct was isolated in thesame manner'as disclosed in'Example '1, partD. The product, 1-methyl-3-(2-benzylamino-l-hydroxyethyl) indole, wasrecrystallized three times from ethyl acetate and melted at' 1111'13fdegrees centigrade.

Analysis-Calcd-forC H N oz C, 77.11; H, 7.19; N, 9. 99. Found C, 76.83;H, 7.28;N, 9.86.- I EXAMPLE 5 .-PREPARATION or 1-ETHYL-3-(2-DIMETHYL- sINo-1-'HY1 RoxYnrHYL).-IrxnoLe AND SALTS THEREOF A.N,N-dimethyl-3-indoleglyoxylamide A s'uspensionof fortygrams (0.2 mole)of 3-indoleglyoxylyl chloride, prepared as disclosed in Example 1; partA, in 500 milliliters of; dry benzene was saturated with gaseousdimethylamine for two hours. A clear solution resulted. Thebenzene wasconcentrated, and the solid residue slurried with water to dissolvedimethylamine hydrochloride. Theinsoluble residue was filtered and re'-'crystallizedfirst from isopropanol-waterand finally from methyl,cyclohexane-ethyl acetate. The product, 'N,N.- dimethyl 3indoleglyoxylamide, melted at 159-160 de? grees centigrade and weighed38 grams (88 percent yield). 7

.Analysis-Czilcd. for C H N O C, 66.65; H, 5.59; N, 12.96. Found: C,66.96; H, 5.85 N, 13.26;

. B; 1-ethyl-N,N-dimethyl-3-ind0leglyoxylamide 1 A solution of 4.6 grams(0.2 mole) of sodiumin 800 milliliters of absolute ethanol waspreparedand'to this was added 32.4 grams (0.15 mole) of N,N-dimethyl-3-indoleglyoxylamide. The solution was placed in a pres surefiask and23.38 grams (0.15 mole) of ethyl iodide added. This mixture was heatedat eighty degrees centigrade for 72 hours. The solution was concentratedand the residue shaken with water to remove sodium iodide. The organicresidue was recrystallized from aqueous ethanol- The product,1-ethyl-N,N-dimethyl-3-indoleglyoxylamide, melted at 141-143 degreescentigrade.

, Analysis.-'-Calcd. for C H N O C, 68.83; H, 6.60; N, 11.74. Found: C,68.62 H, 6.47;'N, 11.76. a

, 200 milliliters of tetrahydrofuran. The mixture was re-.

fiuxed for three hours and cooled overnight. The excess lithium aluminumhydride was destroyed with 500 milliliters of USP etherfollowed by fiftymillilitersoften' percent sodium hydroxide solution. The solvent layerwas decanted and concentrated. The solid obtained was twicerecrystallized from ethyl acetate to yield 4.81 grams (52 percent) of1-ethyl-3-(Z-dimethylamino-l-hydroxyethyl)- indole which melted at 82-83degrees centigrade.

. Analysis-Calm. for CHH N O: C, 72.38,; H, 8.68; N,12.06. Found:C,72.'54; H,'8.57;'N, 11.86. i i

- dimethylam'ino I hydroxyethyl) indole .pyruvate e To 100. milligrams10f '1 ethyl 3 (Zdiniethylaminofle igdroxyethyD-indole in twentymilliliters; of anhydrous; 7 ether was. added 135. milligrams of pyruvicacid in one milliliter of ether. "A white solid precipitate, -ethyl-3-(Z-dimethylainind-l-hydroxyethyl)-indole pyruvate, was

obtained which foamed at 1125 degrees centigrade and melted at 116degrees centigrade. 7

Analysis.--Calcd. for C H N O C, 63.75; 11,754; N,'8.53. Found C, 64.20;H, 7.71; N, 8.63.; I i V E. 1 ethyl 7 3 (2 dimethylam-in'o hydroxyethyl) I indole trichloroacetate V ,3 To milligrams of lethyl-S-(Z-dimethylarnino-l hydroayethyD-indole in twenty milliliters ofanhydrous ether was added 65 milligrams of trichloroacetic'acid onemilliliter of ether. 7 The resulting precipitate, l-ethyl-3-(2-dimethylamino-1-hydroxyethyl)-indole trichloroacetate, weighedmilligrams and melted at 92' to 95.5, degrees centigrade.

F. I ethyl 3 (2 dimethyhimino 1 hydmxyethyl) indole hydrochloride isticky solid precipitated which was washedfwith ether and dried to yieldcrystalline 1-ethyl-3-(2-dimethylamino 1 -hydroxyetliyl) indolehydrochloride, which melted with decomposition at 108.5 to 111 degreescentigrade. a e

EXAMPLE 6.-Pimpm'rroi-z 0F mama- H el HYDROXYETHYL)INDOLE A. 3-indoleglyoxylamide 7 Tea 25 gram sample of indole dissolved milliliters ofanhydrous ether at room temperature was added After the v so ous r 25milliliters of oxalyl chloride.

action had subsided the precipitate was filtered and.-

washed with ether. The V precipitate, 3 indoleglyoxlyl chloride, wasadded to 700 millilitersof anhydrous; ether in a one-liter flask andcooled .to between zero degrees and ten degrees'centigrade; Anhydrousammonia was added thereto with stirring until the 'yellow colordis- Vappeared, the precipitate stirred for itwo'additiolial hours; slurriedone hour in 500 milliliters of water, and then the precipitate wascollected and washedlthoroughly with water. After drying theS-indoIegIyoxyIamideweighed 33.7 grams (92.4 percent). T

B. I-methyl-j indolegiybxy amide A solution of sodium ethoxidewasprepared from 525' milliliters, of absolute ethanol and three: grams1 (0.13

mole) of sodium. Tothis sol'ution in a pressurebottle was added 22.5grams (0.12. mole), of 3 indoleg lyokyl amide and 18.7 grams. (0.13mole) oimethyliodide. The mixture was heated at 75 80 degrees centigradefor eighteen hours. The alcohol was distilled and the residuerecrystallized from isopropanol; The produet, 1-methyle3-indoleglyoxylamide, weighed nineteen grams and melted;

at 187 degrees centigrade. V 7 7 Analysis. Calcd. for (l H-mN Q 'z C,65.33; H, 49 8;

' C. '1 -me tl zyl-3-(Z-qminb-l-hydroxyethyl)-indoie Ten grams; (0.05mole) of 1-methyl 3-indoleglyoxylamide was dissolved in tetrahydrofuran7.4 grams (0.2 mole) of lithiumaluminum hydridejin 200 milliliters oftetrahydrofuran. The mixturewaste; fluxed for three'hours, cooled, and.thecix QessLlithium aluminum hydride, was destroyed with USP ether fol:4

lowed by ten percentsodium. hydroxidesolution, -Theconcentration of thesolvent gave 1- ethyl:3-(2'-'amino;;

and added to" EXAMPLE 7 .-PREPARATION OF 1-MEmYL-3-(2-DmnNzYL-AMINO-l-HYDROXYETHYL)-INDOLE A. N,N-dibenzyl-i-indoleglyoxylamide B.1-methyl-N,N-dibenzyl-3-indoleglyoxylamide A solution of sodium ethoxidewas prepared through the addition of 2.3 grams (0.1 mole) of sodium to250 milliliters of absolute ethanol. To this solution was added eighteengrams (0.1 mole) of N,N-dibenzyl-3- indoieglyoxylamide and twenty grams(0.14 mole) of methyl iodide. This mixture was heated at 75 degreescentigrade for eighteen hours in a pressure flask. The solvent wasconcentrated and water added to dissolve the sodium iodide. Theresulting gum crystallized slowly and was recrystallized fromisopropanol. The product, 1-methyl-N,N-dibenzyl-3-indoleglyoxylamide,melted at 109-111 degrees Centigrade.

Analysis-Calcd. for C H N O C, 78.49; H, 5.79; N, 7.32. Found: C, 78.85;H, 5.79; N, 7.38.

C. 1 -methyl-3- (Z-dibenzy lamina-1 -hydroxyethyl) -indle Seven grams(0.018 mole) of 1-methyl-N,N-dibenzyl- S-indoleglyoxylamide in fiftymilliliters of tetrahydrofuran was added to live grams (0.135 mole) oflithium aluminum hydride in 100 milliliters of the same solvent. Afterrefluxing for two hours the mixture was cooled in an ice-bath and 500milliliters of USP ether added. After the addition of fifty millilitersof ten percent sodium hydroxide solution the solvent layer was decanted.Concentration of the solvent layer gave a solid which was crystallizedtwice from ethyl acetate. The yield of1-methyl-3-(Z-dibenzylamino-l-hydroxyethyl)-indole was 4.5 grams (67.5percent) and the product melted at 120.5-122 degrees centigrade.

Analysis.Calcd. for C H N O: C, 81.04; H, 7.07; N, 7.56. Found: C,81.29; H, 6.90; N, 7.59.

EXAMPLE 8.PREPARATION OF 1-ME'l'HYL-3-(2-ANILINO- l-HYDROXYETHYL) INDOLEA. N-phenyl-S-indoleglyoxylamide Twenty grams (0.1 mole) of3-indoleglyoxylyl chloride prepared as described in Example 1, part A,was suspended in benzene and 18.6 grams (0.2 mole) of aniline added.After three hours the heavy precipitate was filtered, washed well withwater to remove aniline hydro cluoride, and the residual solidrecrystallized from isopropanol. The yield ofN-phenyl-3-indoleglyoxylamide was 26.4 grams (100 percent) and theproduct melted at 242-243 degrees centigrade.

Analysis.Calcd. for C H N O C, 72.71; H, 4.58; N, 10.60. Found: C,72.58; H, 4.45; N, 10.78.

B. 1-mezhyZ-N-phenyl-3-indoleglyoxylamide A solution of sodium ethoxidewas prepared from 3.45 grams of sodium and 500 milliliters ofabsolute'ethanol. To this solution was added twenty grams (0.76 mole) ofN-phenyl-3-indoleglyoxylamide and 21.6 grams (0.15 mole) of methyliodide. This mixture was heated for 36 hours at 65-75 degrees centigradein a pressure bottle. The solvent was then concentrated and the residuerecrystallized from ethanol. The product, l-methyl-N-phenyl-3-indoleglyoxylamide, separated as long needles and melted at150-152 degrees centigrade.

Analysis.-Calcd. for C H N O C, 73.36; H, 5.07; N, 10.07. Found: C,73.49; H, 4.84; N, 9.97.

C. 1 -methyl-3- (Z-ani lino-1 -hydroxyethyl -ind0le In the same manneras disclosed in Example 7, part C,1-methyl-N-phenyl-3-indoleglyoxylamide was reduced with lithium aluminumhydride to yield .1-methyl-3-(2- anilino-l-hydroxyethyl)-indo1e. v 1

EXAMPLE 9.-PREPARATION OF 1-MErnYL-3-(2-Dr- METHYLAMINO- 1-HYDROXYETHYL) -INDOLE A. 1,N,N-trimethyl-3-ind0legly0xylamide In thesame manner as disclosed in Example 5, part B,1,N,N-trimethyl-3-indoleglyoxylamide was prepared by reactingN,N-dimethyl-3-indoleglyoxylamide with methyl iodide instead of ethyliodide. The compound melted between 107.5-108.5 degrees centigrade.

Analysis.Calcd. for C I-1 N 0 C, 67.83; H, 6.13; N, 12.17. Found: C,67.78; H, 5.98; N, 12.35.

B. 1 -methyl-3-(Z-dimethylamino-l -hydroxyethyl -ind0le In the samemanner as disclosed in Example 5, part C,1,N,N-trimethyl-3-indoleglyoxylamide was reduced with lithium aluminumhydride to produce l-methyl-3-(2-dimethylami-no-l-hydroxyethyl)-indolewhich melted between 94-95 degrees centigrade.

Analysis.Calcd. for C H N O: C, 71.52; H, 8.31; N, 12.83. Found: C,71.96; H, 8.07; N, 12.36.

EXAMPLE 10.-PREPARATION OF 1-EmYL-3-(2-ME1HYL- AMINO-1 -HYDROXYETHYL)-1NDOLE A. 1-ethy1-N-methyl-3-ind0legly0xylamide In the same manner asdisclosed in Example 1, part C, l-ethyl-N-mcthyl-3-indoleglyoxylamidewas prepared by employing ethyl iodide in lieu of methyl iodide. Thecompound melted between -125] degrees centigrade.

Analysis. Calcd. for G i-1 N 0 C, 67.85; H, 6.12; N, 12.16. Found: C,67.32; H, 5.96; N, 12.43.

B. 1-ethyl-3- (Z-methylamino-l-hydroxyethyl) -indole In the same manneras disclosed in Example 1, part D, 1-ethyl-N-methyl-3-iudoleglyoxylamidewas reduced with lithium aluminum hydride to produce1-ethyl-3-(2-methylamino-l-hydroxyethyl)-indole.

EXAMPLE 11.PREPARATION 0F l-ISOPROPYL-3-(2-DI- METHYLAMINO- 1-HYDROXYETHYL) -INDOLB A. 1-is0pr0pyl-N,N-dimethyl-3-indoleglyoxylamideIn the same manner as disclosed in Example 5, part B,l-isopropyl-N,N-dimethyl-3-indoleglyoxylamide was prepared by reactingN,N-dimethyl-3-indoleglyoxylamide with isopropyl iodide instead of ethyliodide. The compound melted between 113-1145 degrees centigrade.

, Analysis.Calcd. for C H N O C, 69.74; H, 7.02; N, 10.85. Found: C,69.52; H, 6.64; N, 10.59.

B. 1-is0propyl-3- (Z-dimethylamino-I-hydr0xyethyl) indole In the samemanner as disclosed in Example 5, part C,1-isopropyl-N,N-dimethyl-3-indoleglyoxylamide was reduced with lithiumaluminum hydride to produce l-isopropyl-3 (Z-dimethylamino- 1-hydroxyethyl) -indole.

EXAMPLE 12.PREPARATION 0F l-BUTYL-3-(2-DIMETHYL-AMINO-l-HYDROXYETHYL)-1NDOLE A.1-butyl-N,N-dimethyl-3-ind0legly0xylamide In the same manner asdisclosed in Example 5, part B,1-butyl-N,N-dimethyl-3-indoleglyoxylamide was prepared by reactingN,N-dimethyl3-indoleglyoxylamide with butyl iodide instead of ethyliodide. The compound melted between 57.5-59 degrees centigrade.

Analysis.-Calcd. for C H N O C, 70.55; H, 7.40; N, 10.28. Found: C,70.85; H, 7.42; N, 10.32.

B. 1-butyl-3- (Z-dimethylamino-I-hydroxyethyl)-ind0le In the same manneras disclosed in Example 5, part C,l-butyl-N,N-dimethyl-3-indoleglyoxylamide was reduced with lithiumaluminum hydride to produce 1-butyl-3-(2-dimethylamino-l-hydroxyethyl)-indole.

'in fifty milliliters of dry ether.

5 EXAMPLE I3.PREPA R ATION OF 1 -HExY 3-(2-DIMnmYL- 7AMrNo-l-Hyrinoxyn'rrirm-lrrnom A.I-hexyl-N,N-dimethyl-S-inddeglyoxyZamide Inthesame manner as disclosedin Example 5, part B, 1-hexyl-N,N-dimethy1-3-indoleglyoxylarnide wasprepared by reacting .N,N-dirnethyl-3-indoleg1yoxylamide with hexyliodide instead of ethyl iodide. The compound melted between 58.5-61degrees-centigrade. I Analysis- Calcd. for 'C gH N O C, 72.45; H, 7.43;N, 9.39. Found: C, 72.38; H, 7.46, N, 9.32.

B; -hexyl-3- (Z-dimethylamino-I -hydroxyethyl) -ind0le In the samemanner as disclosed in Example 5, part C,1-heXyl-N,N-dimethyl-3-indoleglyoxylamide was reduced with lithiumaluminum hydride to produce 1-hexyl-3-(2-dimethylamino-l-hydroxyethyl)-indole.

EXA PLE 14.-PRnPx xrroN or 1-HEXADECYL-3-(2-DI-METHYLAMINOel-HYDROXYETHYL)-INDOLE A.1-hexadecyl-N,N-dimethyl-3-ind0legly0xylamide In the samemanner'asidisclosed in Example 5, part B,

. 1-hexadecyl N,N-dimethyl 3'-indoleglyoxylamide was, prepared byreacting N,N dimethyl 3 7 indoleglyoxylamide with l-iodohexadecaneinstead of ethyl iodide. The compound melted between 61.563 .5 degreescentigrade. Analysisr-Calcdfor C H N O C, 7 6.31, H, 10.C-6;

" 6.35. Found: C, 7 6.60; H, 10.06; N, 6.15

B. 1-hexadecyl- 3- (2 dimethyIqmin0-1-hydr0xyethyl) p 4 indole. In thesame manner'as-disclosed'in Example 5,--part.C,

. 1-hexadecyl-N,N-dimethyl-3-indoleglyoxylamide was. re-

duced with lithium aluminum hydride' to produce 1-hex-' adecyl-3-(Z-dimethylamino-l-hydroxyethyl) -indole which melted between4S49.5"degrees centigrade.

Analysis. Calcd. for c gng mo; c, 78.44; H, 11.23;

N, 6.53. Found: C, 78.80; H, 11.27; N, 6.58. EXAMPLE 15.-PREPARATION 0F1-METHYL-3-(2-IsoPR0- PYLAMINQ-l-HYDROXYETHYL)-INDOLE 7 A.1-mthyl-3-indoleglyoxylyl chloride 7 In a SOO-miIliIitenone-neck flaskc'ooled'ir'i an ice-bath were'placed'13.1 grams (0.1 mole) ofI-methylindole and 200'milliliters of dry ether. 'To this solution wasadded 14 grams. (0.11 mole) of oxalyl chloride dissolved A bright yellowsolid precipitated immediately and after standing in the icebath for onehour the solid material was collected ona filter, washed, with dry etherand placed in a vacuum desiccatorover phosphorus pentoxideQ The driedproduct, l-rnethyl-3-indoleglyoxylyl chloride, weighed 15.4 grams(seventy percent yield). 7

' A solutio n of 8.5[ grams (0.144 mole) of isopropylamine andmilliliters of benzenewas added overthl'rty lized from ethyl acetate toyield 2.5 grams (35.7 peryield 16.4 gramsof1-methyl-2-phenyl-3-indoleglyoxylic' minutes to a Suspensionof10.6'grams (0.048 moleyof 1-methyl-3 -indoleglyoxylyl; chloride and 25-milliliters of benzene. The suspension was stirred for one and one-halfhours until the. yellow color had disappeared. The benzene was removedunder reduced pressure and the residue slurried in water. Theslurriedresidue was placedin an 'ice batl1 whereupon crystallization occurred,and the solid was removed and recrystallized from approximately 7percent alcohol.

The. product, 1-methyl-N-isopropyl-3- melted at 103-1045 degreescentigrade. V Analysis.-Calcd'.'for C I-1 N 0 0.68.82; H, 6.60;

roe. ,Eound: 0,5957; H, 6.62;'N,.11.21.

indoleglyoxylamide, weighed 9.7 grams 7 f C: I-rn thyl-d-(Z-kbpropyiarizino-I-hyciroxyethyij5 7.

solutionef 6.9 grams (0103' mole) of .l-methyl-N 7isopropyl-3indolglyoxylamide and milliliters tetra 83 percent) and Vcent) of '1-methyl-3-(2-isopropylamino-l-hydroxyethyl)- indole whichmelted at 114.5115.5 degrees centigrade.

Analysis.Calcd. for C H N Oz C, 72.38; H, 8.67; N,

12.06. Found: C, 72.63; H, 8.32; N, 11.88.

EXAMPLE 16.-PREPARATION or l-METHYL-ZrPHENYL-Ii-(Z-PIPERIDINQ-l-HYDROXYETHYL)-INDOLE A. I methyl-Z-phenyl-3ind0legly0xyiyl chloride In the same manner as disclosed in Example 15,part- A, 1-methyl-2-phenyl-3-indoleglyoxylyl chloride Was prepared byemploying l.-methyl-2-phenylindole as the starting compound instead 'ofl-methylindole.

B. 1Tmethyi-Z-phenyl-Qi-indblegly'oxylic acid pip e rzdide To a solutionof 14.8 grams (0.05 mole) of l-methyl- 2-phenyl-3-ind'oleglyoxylylchloride in 200 milliliters of dry benzene was added thirteen grams(0.15 mole) of piperidine. Vigorous reaction ensued and a precipitatethereuponseparated. After standing {or 72 hours the mixture was filteredand the filtrate concentrated. The remaining solid was recrystallizedfrorn' isopropanol to acid piperidide which melted V at 159-160 degreescentigrade.

N, 8.08. Found: C, 76.44; H, 6.22; N, 826.

. C. 1-methyl-2-phenyl-3-(Z-piperidino-I-hydr0xyethyl) 40 2' iindole VNine grams (0.026 molel-of I-methyl-Z phenyI-S-indoleglyoxylic acid.piperidide was dissolved in 100 milli liters oftetrahydrofu'ran'and theresulting solution was added to five grams (0.135 mole) of'lithiumaluminum hydride in 100 milliliters of the same solvent. The mixture wasrefluxed for three'hours and cooled in an icebath. The mixture wastreated with 500 milliliters of U. S. P. ether: and fifty milliliters often percent sodium hydroxide solution. The'solvent layer was'decantedand the. alkali layer washed with several 100-milliliter portions ofether. The combined solvents were concentrated under reduced pressure.The residue crystallized and was recrystallized several times from ethylacetate. The prod-.

not, 1 methyPZ-phenyl-B-(2-piperidino 1-hydroxyethyl')3 indole, meltedat 154.5-156 degrees centigrade.

N; 8.37. Found: C, 79.01; H, 7 .70; N, 3.29.

In the same manner as'disolosed in Example '15, 1-'

' methyl-3-indoleglyoxylyl chloride was prepared andfreacted withammonia 'instead of isopropylamine; to; "pro;-

EXAMPLE duce 1-methyl-3-indoleglyoxylamide,' and the latter was reducedwith lithium aluminum hydride to 'producelmethyl-3-(2-amino-l-hydroxyethyl) -indole.

zyl-3 indo leglyoxy1yl chloride was Analysis.-Calcd. for c n mo i c,76.27; H, 6.40;

prepared by utilizing l-benzylindole. instead of l-methylindoles Thethus produced compound was reacted with ethylamine instead.

. ofisopropylamine to produce 1;benzyl-N-ethy1-3-in- .doleglyoxylamide,and the latter was reduced with lithium aluminum hydride to producel-benzyl-3-(2-ethylamino- 1-hydroxyethyl)-indole.

EXAMPLE 19.-PREPARATION OF 1,2-DrernYL-3-(2-DI- BUTYLAMINO- 1-HYnRoxYErnYL) -1NDOLE In the same manner as disclosed in Example 1,part C, 1,2-diethylindole was prepared by reacting 2-ethylindole withethyl iodide in lieu of N-methyl-3-indoleglyoxylamide and methyl iodide,and the thus-produced compound was reacted with oxalyl chloride toproduce 1,2- diethyl-3-indoleglyoxylyl chloride. The1,2-diethyl-3-indoleglyoxylyl chloride was reacted with dibutylamiue toproduce 1,2-diethyl-N,N-dibutyl 3 indoleglyoxylamide, and the latter wasreduced with lithium aluminum hydride to producel,2-diethyl-3-(Z-dibutylamino-l-hydroxyethyl)-indole.

EXAMPLE 2Q.-PREPARATION F 1-HExYL-6-BENzYLoxY-3-(Z-BENZYLAMINO-1-HYDROXYETHYL) {more In the same manner as disclosed inExample 1, part C, 1-hexyl-6-benzyloxyindole was prepared by reacting 6-benzyloxyindole with hexyl iodide in lieu of N-methyl-3-indoleglyoxylamide and methyl iodide.

In the same manner as disclosed in Example 15, part A,1-hexyl-6-benzyl0xy-3*indoleglyoxylyl chloride was prepared by reactingoxalyl chloride and 1-hexyl-6-benzyloxyindole. The resulting compoundwas reacted with benzylamine to produce 1-hexyl-6-benzyloxy-N-benzyl-3-indoleglyoxylamide, and the latter was reduced with lithium aluminumhydride to produce 1-hexyl-6-benzyloxy-3 (2-benzylaminol-hydroxyethyl)-indole.

ExAMPLE 21.PREPARA'I'ION 0F LZ-DIPROPYL-fi-(PARA,

PARAI-DIME'H'IYLBENZHYDRYLOXY) -3-(2-BUTYLAMINO-1- HYDROXYETHYL)-lNuor.E 4-hydroxy-2-nitrobenzaldehyde was refluxed withdiparatolylbromomethane [1. Am. Chem. Soc. 55, 2135 (1933)] and sodiumethoxide in absolute ethanol to produce 4(para,para'-dimethylbenzhydryloxy)-2-nitrobenzaldehyde. Thethus-produced compound was condensed with l-nitrobutane in ethanol andwater in the presence of sodium hydroxide at about minus fifteen degreescentigrade. The mixture was acidified with acetic acid, and theresulting product,4-(para,para-dimethylbenzhydryloxy)-2-nitro-u-[l-(l-nitrobutyl)]-benzylalcohol, was removed by filtration and dehydrated with acetic anhydrideat about eighty degrees centigrade. The resulting4-(para,para-dimethylbenzhydryloxy)13,2 dinitro-fi-propylstyrene wasreductively cyclized with powdered iron in acetic acid at about 85degrees centigrade to produce2-propyl-6-(para,para'-dimethylbenzhydryloxy-indole.

In the same manner as shown in Example 1, part C, 1,2dipropyl-6-(para,para'-dimethylbenzhydryloxy) indole was prepared byreacting 2-propyl-6-(para,para'- dimethylbenzhydryloxy)-indole withpropyl iodide in lieu of N-methyl-3-indoleglyoxylamide and methyliodide.

In the same manner as disclosed in Example 15, part A,1,2-dipropyl-6-(para,para dimethylbenzhydryloxy)- 3-indoleglyoxylylchloride was prepared by reacting oxalyl chloride and1,2-dipropyl-6-(para,para'-dimethylbenzhydryloxy)-indole. The resultingcompound was reacted with butylamine to produce1,2-dipropyl-6-(para,paradimethylbenzhydryloxy) Nbutyl-3-indoleglyoxylamide, and the latter was reduced with lithiumaluminum hydride to producel,2-dipropyl-6-(para,para'-dimethylbenzhydryloxy)-3-(2-butylamino-l-hydroxyethyl-indole.EXAMPLE 22,-PREPARATION on l-(PARA-METHOXYBEN- ZYL)--(PARAMETHOXYBENZYLOXY)-3-(2 DIMETHYL- AMINO- 1-HY'DROXYETHYL) -INDOLE In thesame manner as shown in Example 21,l-(paramethoxybenzyl)-5-(para-methoxybenzyloxy)-indole was prepared byreacting 5-hydroxy-2-nitrobenzaldehyde with 4-methoxybenzyl chloride toproduce S-(para-methoxybenzyloxy)-2-nitrobenzaldehyde, condensing theS-(paramethoxybenzyloxy-Z-nitrobenzaldehyde with nitromethane,dehydrating the resulting benzyl alcohol, reductively cyclizing thethus-produced 5-(para-methoxybenzyloxy)- 13,2-dinitrostyrene to produce5-(para-methoxybenzyl oxy)-indole, and reacting the thus-produced indolewith 4-methoxybenzyl chloride.

In the same manner as disclosed in Example 15, part A,l-(para-methoxybenzyl) 5 (para-methoxybenzyloxy)-3-indoleglyoxylylchloride was prepared by reacting oxalyl chloride andl-(para-methoxybenzyl)-5-(paramethoxybenzyloxy)-indole. The resultingcompound was reacted with dimethylamine to producel-(para-methoxybenzyl-5-(para-methoxybenzyloxy) LNdimethyl-3-indoleglyoxylamide, and the latter was reduced with lithiumaluminum hydride to produce 1-(para-methoxybenzyl)-S-(para-methoxybenzyloxy) 3 (Z-dimethylamino-l-hydroxyethyl-indole.

EXAMPLE 23.--PREPARATION OF 1,2-DIOCTYL-6-(PARA-METHYLBENZYLOXY)-3-(Z-ANILINO-1-HYDROXYBTHYL)- INDOLE In the same manneras shown in Example 21, 2,2-dioctyl-6-(para-methylbenzyloxy)-indole wasprepared by reacting 4-hydroxy-2-nitrobenzaldehyde with w-chlorop-xyleneto produce 4-para-methylbenzyloxy)-2-nitroben' zaldehyde, condensing the4-(para-methylbenzyloxy)-2- nitrobenzaldehyde with l-nitrononane,dehydrating the resultlng benzyl alcohol, reductively cyclizing thethus-produced 4 (para-methylbenzyloxy)-fi,2-dinitro-B-octylsty rene toproduce 2-octyl-6-(para-methylbenzyloxy)-indole, and reacting thethus-produced indole with l-chlorooctane. l

in the same manner as disclosed in Example 15, part K, 1,2dioctyl-6-(para-methylbenzyloxy)-3-indoleglyoxylyl chloride waspreparedby reacting oxalyl chloride and1,2-dioctyl-6-(para-methylbenzyloxy)-indole. The resulting compound wasreacted with aniline to produce 1,2- dioctyl 6 (pararnethylbenzyloxy)-N-phenyl-3-indoleglyoxylamide, and the latter wasreduced with lithium aluminum hydride to produce1,2-dioctyl-6-(para-methylbenzyloxy) -3- (Z-anilinol-hydroxyethyl)-indole.

EXAMPLE 24.-PREPARATION 0F l-(PARA-CHLOROBEN- ZYL) -6-(PARA-CHLOROBENZYLOXY) -3- (Z-PROPYLAMINO- 1-HYDROXYETHYL) -lNDOLE Inthe same manner as shown in Example 21, l-(parachlorobenzylj-o-(para-chlorobenzyloxy)-indole was prepared by reacting4-hydroxy-2-nitrobenzaldehyde with 4-chlorobenzyl bromide to produce4-(para-chlorobenzyloxy)-2-nitrobenzaldehyde, condensing the4-(para-chlorobenzyloxy)-2-nitrobenzaldehyde with nitromethane,dehydrating the resulting benzyl alcohol, reductively cyclizing the thusproduced 4-(para-chlorobenzyloxy)- 8,2-dini trostyrene to produceo-(para-chlorobenzyloxy)-indole, and reacting the thus-produced indolewith 4-chlorobenzyl bromide.

In the same manner as disclosed in Example 15, part A,l-(para-chlorobenzyl)-6-(para-chlorobenzyloxy) 3 indoieglyoxylylchloride was prepared by reacting oxalyl chloride and 1-(para-chlorooenzyl) -6-(para-chlorobenzyloxy)-indole. The resultingcompound was reacted with propylamine to producel-(para-chlorobenzyl-G-(parachlorobenzyloxy)-N-propyl-3-indoleglyoxylamide,and the latter was reduced with lithium aluminum hydride to produce1-(para-chlorobenzyl)-6-(para chlorobenzyloxy)-3-(Z-propylamino-l-hydroxyethyl)-indole.

EXAMPLE 25.-PREPARATION on l-EIHYL-Z-PHENYL-S- ETHOXY 3 (2HEXAME'I'HYLENEIMINO -1- HYoRoxY- ETHYL)-INDOLB In the same-manner asdisclosed in Example 15, part A,1-ethyl-2-phenyl-5-ethoxy-3-indoleglyoxylyl chloride was prepared byreacting oxalyl chloride with 1-ethyl-2- phenyl-S-ethoxyindole (J. Chem.Soc. 1944, 670). The resulting compound was reacted withhexamethyleneimine to produce1-ethyl-2-phenyl-5-ethoxy-N-hexamethylene-S-indoleglyoxylamide, and thelatter was reduced with lithium aluminum hydride to produce1-ethylassess;

:2-phenyl ethoxy-3-(Z-hexamethyleneiinino 1 hydroxyethyD-iridole. V

EXAMPLE, ila-PREPARATION or l-(PARh-ME'IHYLBEN- zL)'-5,6-DnrYnRoxY-3-(2- BENZYLMETHYLAMINO-l-HY- DROXY)-INDOLE In thesamemanner as shown in Example 21, l-(paramethylbenzyl)5,6-diacetoxy73-indoleglyoxyly1 chloride was prepared by reactingw-chloro-p-xylene with 5,6-diacetoxyindole (LChem. Soc. .1948, 2223) andreacting the thus-produced vl-(para-methylbenzyl) 5,6-diacetoxy- Vindole with oxalyl chloride. The resulting compound Soc. 1948(847) andB-phenethyl chloride to produce lphenethyl-Lphenyl-S-chlomindole andreacting the thusproduced compound with oxalyl chloride. *Thel-phenethyl-2-phenyl-5 chloro-3-indoleglyoxylyl chloride was reactedwith methylamine' to produce l-phenethyl-Z-phenyl-5-chloro-Nernethyl-3-indoleglyoxylamide, and the latter Wasjreduced withlithium aluminum hydride to produce 1-phenethyl-2rphenyl-5-chloro-3(Z-methylamino -'l hydroxyethyD-indole.

EXAMPLE '28.:-PREPARATION 'OF l-(PARA-METHYLBBN- zYL)-2-PR0PYL-6-AM1N0METHYL-3- Z-BENZYLAMINO- 1- HYDROXYETHYL).INDOLE In thesame manner as shown in Example 21,l-(paramethylbenzyl)-2-propyl-6-cyanoindole was prepared by condensing4-cyano-2 -nitrobenzaldehyde (J. Chem. Soc. 1946, 567) withl-nitrobutane; dehydrating the resulting benzyl alcohol, reductivelycyclizing the thus-produced 4- cyano-B,2-dinitro-,3-propylstyrene toproduce 2-propyl-6- cyanoindole, and reacting the thus-producedindolewith w-chloro-p-xylene. u r

In the same; manner as disclosed A,l-(para-methylbenzyl)-2-propyl-6-cyano 3 indoleglyoxylyl chloride wasprepared by. reacting oxalyl chlo ride and I l;(para-methylbenzyl)-2-propyl-6-cyanoindole.

.The resulting compound was reacted with benzylamine to produce.1-(para-methylbenzyl) 2-propyl 6 -cyano-N- benzyl 3-indoleglyoxylamide, and the latter was reduced with lithium aluminumhydride to produce l-(paramethylbenzyl)-2-propyl6 -aminomethyl 3(2-benzylamino-l-hydroxyethyl)-indole. 7 7

EXAMPLE '29.-PRE 1 ARAnoN 0F 1-DECYL-4-MEI'HYLOL-3- Y(Z-PIPERHJINO-l-HYDROXYE'I'HYL)-INDOLE In the. same mannergas shown inExample 21, 1-decyl-,

4-carbomethoxyindole was prepared by condensing '6-carbomethoxy-Z-nitrobenzaldehyde (Monat. 24, 838) with 'reductivelycyclizing the thus-produced 6-carbomethoxyfi,2-dinitrostyrene to produce4-carbomethoxyindole; and

reacting Lthe thus-produced indole with -lc-chlorodecane.

In 'theisamemanner as disclosed in Example 15, part v 4 z o namesot-PREPARATION or I-PHENEmYL-Z-EmYL-T INnorlE In the same manner asshown in Example 21, l-phenethyl-2-ethyl-fi-carboxyindole was preparedby'condensing 4-cmbQXy-Z-nitrobenZaIdehyde (Ann. 231; 368) withlnitropropane', dehydrating the resulting benzyl alcohol," reductivelycyclizing the thus produced 4-carboxy-p,-2-'

' dinitr o-fl-ethylstyrene to produce 2-ethyl-6-carboxyindo1e in Example15, part a and reacting the thus produced indole with fl-phenethylchloride. 7 u I w In the samemanner as disclosed in' Example 15 part A,l phenethyl-2-ethyl 6-carboxy-3-indoleglyoxylyl chloride was prepared byreacting oxalyl chloride. and l-phen The resulting compoundethyl-2-ethyl--carboxyindole. as c ed t p opyla i e q pmd r hen tlly -g:ethyl-6-carboxy-Nepropyl-3-indoleglyoxylamide, ,and the latter wasreduced with lithium aluminum hydride-to produce l-phene thyl -.2ethyl-6-m ethylol-3 (2 propyh amino-l-hydroxye'thyl)-indole. 7 u 7vEXAMPLE 31.- PREPm'r1oN..oF l-OCTYL-G-DIMB'IHYLv AMINO-3-(Z-DIETHYLAINO-1-HYnRoxYETHYL)-INDoLE 6-dimethylaminoindole was prepared byreacting .6- aminoindole U. Am. Chem. Soc. 76, 5149-50 (1954)] withdimethyl sulfate in dilute aqueous sodium hydroxide solution.

do the same manner as disclosed in Example 2l, 6 dimethylaminoindolewasreacted with l-chlorooctane to produce 1=octyl--dimethylaminoindole andthe latter compound was reacted with oxalyl chlorideto producel-octyl-6-dimethylamino-3-indoleglyoxylyl chloride. The

resulting compound'wasreacted with diethylamine. to

produce 1 octyl-6-dimethylamino-N,N-diethyl-B-indoleglyoxylamide, andthelatter was reduced with lithium aluminum hydride to produce 1-octyl-6-dimethylamino-3- (2-diethylamino-l hydroxyethyl)-indole. IEXAMPLE -'32.PREPARATroN on VI-E'IHYIL-Z-PHENYIL-IS-METHYL-3-(Z-ANILINO-l-HYDRQXYETHYL1-INDOLE In the same manner asdisclosed in Example 15, part A, l-ethyla2phenyl-5-methyl-3-indoleglyoxyly11 chloride was prepared by reactingoxalyl chloride with 1-ethyl- Z-phenyl-S-methylindole' (J. Chem. Soc.1943, 58). The

resulting compound was reacted with aniline to produce lethyl-2-phenyl-5-methyl N-phenyl-3-indoleglyoxylamide,

and the latter was reduced; with lithium aluminum hydride to produce lethyl-2 phenyl-5-methyl-3-(2-anilinol-hydroxyethylyindole. V I a 7 E AML ss.,+rtatmnosot 1.-Ba s 5-.D B E 'l N L M. N'1'H B Y PJ D L In thesamemanner as shown in-Example 21,-1-benzyl- 2QS-diphenylindole wasprepared by reacting 2,5-diphenylindole U. Org. Chem. 2,235 (1937)] withbenzyl chloride 1-benzyl-2,5-diphenyl-3-indoleglyoxylylV chloride wasprepared by reacting oxalyl chloride with 1benzylt 2,5-diphenylindole.The resulting compound wasreacted nitromethane, dehydrating theresultingihenz yl alcohoL'j A, l-decyll-carbomethoxy-indoleglyoxylylchloride was, 1

prepared'by reacting oxalyl chloride and. l-decyl-4-car-.bomethoxyindole; l The. resulting compound wasdreacted with piperidine-to, ,prqduce ll-decyl-.4.-carhomethoxy-3 -indoleglyoxylicacidpiper-idide-and the latteriwa s reduced with lithium, aluminum,hydride, to produce 1-decyl4- methyl 01-3 (2-piperidinol-hydroxyethyl)-indole.

v nzrtslzis o e with benzylamineto produce ..l,N-dibenzyl-2,5-diphenyl-I 3-indoleglyoxylamide, and the Jatter was reducedwith lithiumaluminumthydride to produce l-benzyl-2,5-diphenyl-3-(2-benzylamino-l-hydroxyethyD-indole.

In thesamemannenas shown in Example 2 1-,' l-etihyl- 1-benz-(-g)in d0levwas prepared by reactingrethyl chloride and 1-benz-(g)-ind-ole (I.Chem..Soc. 1951, 2462 a.

Inthe same manner as disclosedin Example 15, part A,

PIEPQTBQ krs s q a y fls l r srw h 3 1 x 1 Ihe r ul in s m pu a reacted1 i e lami e to Pro u e L NN st th .1 Pau 3:- nd lyaxyl m d la d t e a ew s; r duc (g) -3- (Z-die thyIamino-I-hydroxyethyl) indole.

G-METIIYLOL-d-(Z-PROPYLAMINO 1 HYDROXYETHYLF seam 34 (Z-GYCLOHEXYLAMINO-l-l-lyunoxyamyr.) Jun OLE 1 The para-phenoxyphenylhydrazo'ne of pyruvicacid, prepared by condensingpyruvic acid and para-phenoxyphenylhydrazine[L' Am. Chem. Soc. 70, 1381 (1948)] was heated with'zinc chloride viathe Fischer indole synthesis to produce S-phenoxyindole. The resultingcompound was reacted with l-chlorodecane to producel-decyl-S-phenoxyindole. V

In the same manner as disclosed 'in Example 15, part A, 1 decyl 5phenoxy 3 indolegiyoxylyl chloride was prepared by reacting oxalylchloride with I-decyl-S-phenoxyindole. The resulting compound wasreacted with cyclohexylamine to produce 1 decyl 5 phenoxy N cyclohexyl 3indoleglyoxylamide, and the latter'was reduced with lithium aluminumhydride to produce 1- decyl 5 phenoxy 3 (2 cyclohexylamino -'1hydroxyethyl) indole.

EXAMPLE 36.PREPARATION OF PHENYLYL) 3 -[2-( BENZYL-Z-E'IHYLHEXYLAMINO)-1-HY- DROXYETHYLl-IND OLE In the same manner as disclosed in Example15,'part A,

oxalyl chloride was reacted with 1-ethyl-2-p-biphenylylindole (J. Chem.Soc. 1948, 847) to produce 1-ethyl-2-pbiphenylyl 3 indoleglyoxylylchloride. The thus-produced compound was reacted withN-benzyl-2-ethylhexylamine, to produce1-ethyl-2-(parabiphenylyl)-Nbenzyl N-(2-ethy1hexyl-3-indoleglyoxylamide,and the latter was reduced with lithium aluminum hydride to produce 1-ethyl 2 (para-biphenylyl) 3 [2 (benzyl 2 ethylhexylamino) 1hydroxyethyl] indole.

EXAMPLE 37.PREPARATION OF 1-BENZYL-2PHENYL-5,7-DrcHLoR-3-(2-ANrLmo-1-HYDnoxYETnYL)-INDoLE 1 benzyl 2 phenyl 5,7dichloroindole. The resulting compound was reacted with aniline toproduce 1- benzyl 2 phenyl 5,7 dichloro N phenyl 3 indoleglyoxylamide,and the latter was reduced with lithium aluminum hydride'to produce 1benzyl 2 phenyl 5 ,7 dichloro 3 (2 anilino 1 hydroxyethyl) indole.

ExAMPLn 38.PREPARATION 0F 1,7-DIBENZYL-3-(2-METHYLAMINO-l-HYDROXYETHYL)-INDOLB 7-benzylindole was prepared byconverting ortho-aminodiphenylmethane (J. Chem. Soc. 1945, 646) to orthohydrazinodiphenylmethane, utilizing the general procedure outlined inOrganic Syntheses, collective volume 1, pages 442-445, and theorthohydrazinodiphenylmethane 'was condensed with ethyl pyruvate,utilizing the well known Fischer indole synthesis, to yield theortho-benzylphenylhydrazone of ethyl pyruvate which was then cyclized,deesterifi'ed, and decarboxylated to yield 7-benzylindole.

In the same manner as shown in Example 21, 1,7-dibenzyl-3indoleglyoxylylchloride was prepared by reacting 7-benzylindole with benzyl chloride,and reactingoxalyl chloride with the resulting 1,7-dibenzylindole. Theresulting compound was reacted with methylamine toproduce 1,7 dibenzyl Nmethyl 3 indoleglyoxylamide, and the latter compound was reacted withlithium aluminum hydride to produce 1,7 dibenzyl 3 (2 methylamino 1hydroxyethyl) indole.

EXAMPLE 39.-PREPARATION or 1-PHENYL-3-L2-(L2-DI- METHYLPYRROLIDINO)-1-HYD 0XYETHYL1-1ND0LB In the same manner as shown in Example 15,--partA,

1-ETHYL-2 PAnA-B1- .had precipitated.

22 1phenyl-3 indoleglyoxylyl chloridewas' prepared by sub= stitutiiig lphenyl-indole (Shirley et a1., locrcit.) for '1- methylindo'le; Theresulting compound was reacted-with 2,2 dim'ethylpyrrolidine to produce1-phenyl-3-indo'1eg1y oxylic acid 2,2-dimethylpyrrolidide, which wasreduced with lithium aluminum hydride to produce 1-phenyl-3- [2-(2,2-dimethylpyrrolidino) -l-hydroxyethyl] -indo1e. EXAMPLE40.PREPARATION 0F 1-E'I'HYL-3-(2-DIMETHYL- AMINO- 1 -HYDROXYETHYL)JNDOLE 1ethyl-N,N-dimethyl-3-indoleglyoxylamide (Example 5, part B) wassuspended in ethanol and shaken under a hydrogen pressure of about fiftypounds in the presence of Adam's platinum oxide catalyst. Whenthe-hydrogen uptake halted the resulting mixture was heatedand'filtered.

The ethanol was removed by distillation to yieldl-ethyl-N,N-dimethyl-3-indoleglycolamide.

In the same manner as shownin Example 5, part C, 1-ethyl-3-(Z-dimethylamino-l-hydroxyethyl)-indole was obtained by reducing1-ethyl-N,N-dimethyl-3indoleglycolamide with lithium aluminum hydride.

EXAMPLE 41.PREPARATION OF 1-E'I'HYL-3-(2-DIMETHYL-AMINO-l-HYDROXYETHYL)-INDOLE METHOBROMIDE Toasolutionof 0.20 gram ofl-ethyl-3-(2-dimethylamino-l-hydroxyethyl)-indole in 72.5 milliliters ofanhydrous acetone was added 1.1 milliliters of cold methyl bromide. Themixture was kept in a tightly closed flask for two'hours at roomtemperature, at which time a gum The mixture was maintained at minusfifteen degrees centigrade for 48 hours, the solvent was decanted andthe gum was triturated with three milliliters of anhydrous ether. Therewas thus obtained 0.17 gram of l ethyl 3 (2 dimethylamino 1hydroxyethyl)- a indole 'methobromide whcih melted with decompositionbetween 178 and 185 degrees centigrade after sintering at slightly lessthan degrees centigrade.

In the same manner other quaternary ammonium salts such as 1 ethyl 3 (2dimethylamino 1 hydroxyethyl) indole ethobromide, 1 ethyl 3 (2dimethylamino 1 hydroxyethyl) indole benzyl chloride are prepared byusing ethyl bromide and benzyl chloride in lieu of methyl bromide;

Other salts which are produced by the present process include1-methyl-3-(Z-nethylamino-l-hydroxyethyl) -indole pyruvate,1-methyl-3-(2-benzyl-methylamino-labydrox-yethyD-indoletrichloroacetate, 1-methyl-3-(2-dibenzylamino-l-hydroxyethyl)-indoledimethyl sulfate, 1-isopropyl-3-(2-dimethylamino-1-hydroxyethyl)-indolemethyl -.para-toluenesulfonate,1-butyl-3-(Z-dimethylamino-l-hydroxyethyl)-indole ethobromide, and thelike.

It is to be understood that the invention is notto-be limited to theexact details of operation or exact-compounds shown and described, asobvious modifications and equivalents will be apparent to one skilled inthe art, and the invention is therefore to be limited only bythe scopeof the appended claims.

I claim:

1. In a process for the preparation of 3-(2-amino-1-hydroxyethyl)-indole including salts thereof, the step of reducing withlithium'aluminum hydride a compound having the formula:

-.= a benzyloxy, an acyloxy radical wherein the acyl suha and mindole'.J

' stituent isfrom an organic carbogzylic acid, and a fused aryleneradical; R iss select'ed from the" group consisting ofan alkyl; aryl,and an aralkyl radical, Z is an amide radical, andYis selected from the*group consisting'of g i t i V '7 V 'e I H 7 v g 7 C- j to produce *a'3-(2 amino-l-hydroxyethyl)-indole.'

2. In a process the steps of "reducing' with' lithium aluminum hydride a3-indoleglyoxylamide having the formula:

t t V 7 "R4 V wherein R is selected from the group consisting ofhydrogen, aryl, aralkyl, and lower-alkyl, n is an" integer from zero tofour, R is selected from the group consisting of carboxy, cyano,dialkylainino;lower-carbalkoxy,

halogen, lower-alkyL'aryl, aralkyl', aryloxy, lower-alkoxy,

'a'benzyloxy,i an' acyloxy radical wherein the acyl substituent isfroman organictcarboxylic acid, and a fused arylene radical, R is selectedfromthe' group consisting of an'alkyl; and, and an aralkyl radicaLf andZ is an amido radical to producega 3 -(2 amino-1 hydroxyethy1)- 3. In aprocess the steps of reacting oxalyl halide with fa'indole having theformula a wherein R is selected from the group consisting of hydrogen,aryl, aralkyl, and lower-alkyl, n'is an integer from zero to four, R isselected from the group consisting of carboxy, cyano, dialkylamino,lower-carbalkoxy,

' halogen, lower-alkyl, aryl, aralkyl, aryloxy, lower-alkoxy,

a benzyloxy, an acyloxy radical wherein, the acyl substituent is from anorganic carboxylic acid, and a fused arylene radical, and R is selectedfrom the group'consisting of an alkyl, aryl, and an aralkyl radicalto'produce a 3-indoleglyoxylyl halide, reacting the 3-indoleglyoxylylhalide with a compound selected from the group consisting of ammonia, aprimary amine, and a secondary amine to produce a3-indoleglyoxylylamide, and reducing the indoleglyoxylamide with lithiumaluminum hydride to produce a 3-(2-amino-l-hydroxyethyl) indole.

4. In a process the steps of reacting oxalyl halide with 1 al-hydroindole having the formula:

\NFRQ 7' wherein R is selected from theil group consisting of hydrogen,aryl, aralkyliand lower-alkyl, n is an integer from zero to four, R isselected from the group consisting of carboxy, cyano, dialkylamino,lower-carbalkoxy,

a 24 ing of ammonia, a primary amine, and -a secondary amine, to producea l-hydro-3-indoleglyoxylamide, re-

actingthe l-hydro-B-indoleglyoxylamide with a compound selected from thegroup consisting of an alkyl halide and an aralkylhalide'irltheprese'nce of an alkali-metal alk} oxide to produce acompound selected from the group consisting of1-alkyl-3-indoleglyoxylamide and l-aralkyl- Q-iridnleglydxylamide, andreducing the compound thus produced with lithium aluminum hydride toproduce a compound selected fromthe groupconsis'ting of l-alkyl-3-(Z-amino-l-hydroxyethyl)-indq1e and 1-aralkyl-3-(2-'amino-1-hydr0xyethyl)-indo1e.

A process for making 1-ethyl-3-(2 dimethylamino- 7l-hydroxyethylkindole'which comprises, the steps of reacting indele withoxalyl chloride to produce 3-indoleglyoxylyl chloride, reacting thethus-produced compound with dimethylaminef to produce 4 N,N-dimethyl-3-indoleglyoxylamide, converting the thus-produced amide to1-ethyl-N,N-dimethyl 3-indoleglyoxylamide by reacting with ethyl iodidein the presence of sodium ethoxide, and

reducing the 1-ethyl-N,N-dimethyl-3-indoleglyoxylamide with lithiumaluminum hydride to produce'l-ethyl-3-(2- dimethylaminol-hydroxyethyl)-indole.

glyoxyl-amide with lithium aluminum hydride to produce a 1-alky1-3-(Z-amino-I -hydroxyethyl -indolek 7. In a process the step of; reducinga l-aryl-3-indoleglyoXyl-amidewith lithium aluminum hydride to produce al aryl-3-(Z-amino-l-hydroxyethyD-indole.

8,111 a process the step of reducing a l-aralkyl-3t-indoleglyoriyl-amidewith lith'ium aluminum hydrideto produce a 1-aralkyl-3-(2amino-l-hydroxyethyl)-indole.

.9. A. process formaking' l-thyl-S-(Z-dimethylamindl-hydroxyethyD-indole which comprises the step'of reducingl-ethyl-N,N+dimethyl-3-indoleglyoxylamide with a lithium aluminumhydride.

10. A compound selected from the group consisting of (l) a3-(Z-amino-Lhydroxyethyl)-indole having the formulas; V 7

OH R7 V a a 'I r g e 7 oH-om-N oi-1m t 5 a a wnerein R is a radicalcontaining not more than 20 carbon atoms and-is selected from the groupconsisting of an alkyl, an arid, and an aralkyl radical, R is a radicalcontaining not more than 15 carbon atoms and is selected from the groupconsisting of hydrogen, aryl', aralkyl, and

lower-alliyl, R is a'radical containing'n'otrnere than 15 carbon atomsand is selected fromrthe group consisting of hydroxy, dia kylarnino,niethylol (CH OH), aminoethyl (CH NH halogen, lo'wer-alkyl, aryl,aralkyl, aryloxy, a fused aiyle'ne, radical, a benzyloxy'radical, and alower-alkoxy radical, 'n is an integer from zerotto four, and R and Rare selected from the group consisting of hydrogen, ar yl aralkyl, andalkyl, and additional members,

of this series wherein R and R together with N .t-form a heterocyclicamino radical, and (2) acid addition and quaternary ammonium saltsthereof.

- j 11. 1-alkyl-3-(Z-dialkylamino-l-hydroxyethyl) indolel V l2; lt-ethyl-3 (2 -'dimethylamino -'l'-hydroxyethyl) indole. 1

' ethyl)-indole hydrochloride.

, 13. 1 ethyl 2 dirn'ethylamino l hydroxyethyD- indole pyruvate. 1

14-; 1 ethyl- 3 2 -diniethylatnirio 1 hydroxyethyl) aindoletrichloroactate. a 1 15; l ethyl 3 (2 dimethjiamino l hydroxy- 16. 1methyl 3 2 dimethylamino i hydroxyethyD-indole, 1;. a

6. In a process the'stepof reducing a 1-alkyl-3-indole-- 17. 1 alkyl 3(2 alkylamino 1 hydroxyethyh- References (Iited in the file of thispatent indole. UNITED STATES PATENTS 18. 1 methyl 3 (2 methylamino 1hydroxyethy1) indo1e 7 2,305,501 splelman Dec. 15, 1942 19. 1 ethyl 3 (2methylamino 1 hydroxyethyD- 5 OTHER REFERENCES indole.

50111. Or vC11ern.,v0. '0, Y 2 es 807 1951 1 methyl 3 (2 morpholmo 1nydroxyethyn' Eour. Chem. 85c: v51. 72, pags 358 6-8 (1950). h 1 3 2 th1 1 h d r T he Chemistry of Heterocyclic Compounds (Indole and at y lmey ammo y roxs' Carbozole) Sumpter et aL, Interscience Publ. Inc., N. Y.

ethyl) -1ndo1e methobrormde. 10

(1954), pages 64 and 69.

Heterocyclic Ccmpeunds, v01. 3, Elderfield, John Wiley and Suns N. Y.,pages 124 and 159 (1952).

1. IN A PROCESS FOR THE PREPARATION OF 3-(2-AMINO-1HYDROXYETHYL)-INDOLEINCLUDING SALTS THEREOF, THE STEP OF REDUCING WITH LITHIUM ALUMINUMHYDRIDE A COMPOUND HAVING THE FORMULA: